Alterations in neuronal voltage-gated K+ channels (Kv) may affect memory disturbances in HIV-1-associated dementia (HAD). Such channel disturbances provide an important explanation for disease reversibility that often follows highly active anti-retroviral therapy. We now posit that the HIV-1 infected and immune competent mononuclear phagocytes (MP; perivascular macrophage and microglia), the natural target cell of virus in brain and the cell responsible for neuronal dysfunction, directly affects neuronal Kv channels and in doing so affects the pathogenesis of HAD. Immunocytochemical, histological, pharmacological and electrophysiological techniques will examine the role of Kv channels in MP-mediated neuronal dysfunction and cognitive impairment in laboratory and animal models of human disease. In addition, we hypothesize that neurons themselves affect MP function leading to a paracrine immune responses between the 2 cells and a subsequent accelerated neuronal impairment. We propose that "diseased" neurons potentiate MP neurotoxin production by enhancing the cells' Kv channel activity. We will test the link between HIV-1- associated alterations in Kv channels and their influence on spatial learning in murine HIV-1 encephalitis (a well established model of human disease). Taken together, these studies are focused toward understanding how HIV-1-infected MPs induce neuronal dysfunction and towards deciphering the underlying channelopathies that affect disease. The abilities to reverse HAD strongly suggests an operative mechanism for inflammatory-mediated reversible neuronal dysfunction. This proposal will begin to examine the pathways for these clinical observations and if successful open the door to the discovery of novel therapeutics to treat neurological disease in affected humans.